| Autor: |
Argiropoulos, Bob, Yung, Eric, Xiang, Ping, Lo, Chao Yu, Kuchenbauer, Florian, Palmqvist, Lars, Reindl, Carola, Heuser, Michael, Sekulovic, Sanja, Rosten, Patty, Muranyi, Andrew, Goh, Siew-Lee, Featherstone, Mark, Humphries, R. Keith |
| Zdroj: |
Blood; May 2010, Vol. 115 Issue: 20 p4071-4082, 12p |
| Abstrakt: |
MEIS1 is a three–amino acid loop extension class homeodomain-containing homeobox (HOX) cofactor that plays key roles in normal hematopoiesis and leukemogenesis. Expression of Meis1is rate-limiting in MLL-associated leukemias and potently interacts with Hoxand NUP98-HOXgenes in leukemic transformation to promote self-renewal and proliferation of hematopoietic progenitors. The oncogenicity of MEIS1 has been linked to its transcriptional activation properties. To further reveal the pathways triggered by Meis1, we assessed the function of a novel engineered fusion form of Meis1, M33-MEIS1, designed to confer transcriptional repression to Meis1target genes that are otherwise up-regulated in normal and malignant hematopoiesis. Retroviral overexpression of M33-Meis1resulted in the rapid and complete eradication of M33-Meis1–transduced normal and leukemic cells in vivo. Cell-cycle analysis showed that M33-Meis1impeded the progression of cells from G1-to-S phase, which correlated with significant reduction of cyclin D3levels and the inhibition of retinoblastoma (pRb) hyperphosphorylation. We identified cyclin D3as a direct downstream target of MEIS1 and M33-MEIS1 and showed that the G1-phase accumulation and growth suppression induced by M33-Meis1was partially relieved by overexpression of cyclin D3. This study provides strong evidence linking the growth-promoting activities of Meis1to the cyclin D-pRbcell-cycle control pathway. |
| Databáze: |
Supplemental Index |
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